Antibiotics Lecture 3 ACU 2025 PDF

Antibiotics LEC. 3: Inhibitors of Nucleic Acid Synthesis Cell Membrane Disruptors Antimetabolites Dr. Rawda Mahmoud Lecturer of Pharmaceutical Chemistry Faculty of Pharmacy, Cairo University 1 Antibiotics course outline Lec.I Cell wall inhibit...

Antibiotics LEC. 3: Inhibitors of Nucleic Acid Synthesis Cell Membrane Disruptors Antimetabolites Dr. Rawda Mahmoud Lecturer of Pharmaceutical Chemistry Faculty of Pharmacy, Cairo University 1 Antibiotics course outline Lec.I Cell wall inhibitors Lec. II Protein synthesis inhibitors Lec. III DNA synthesis inhibitors Antimetabolites Cell membrane disruptors 2  Antibiotics Learning outcomes (Los) By the end of this course, you will be able to : 1-1-4-1 Categorize the provided chemical structure into its pharmacological class and discuss potential pharmacological and therapeutic activities. 1-1-4-2 Apply the basic concepts of stereochemistry to the mode of action of the pharmaceuticals 1-1-4-3 Recognize pharmacokinetic (ADME) and pharmacodynamic properties of the medicines. 2-2-1-1 Select the appropriate methods of synthesis, purification, identification, and standardization of medicines. 3-2-1-2 predict the allergic reactions to some pharmacological compounds 3-2-1-3 Understand and estimate possible pharmacokinetic interactions 3-2-1-4 Understand and estimate the interaction of pharmacological compounds with food 3-2-1-5 Estimate the dosing interval based on the chemical structure 3-2-1-6 Understand the mechanism of action of variable pharmacological entities. 3  Quinolones Beta-Lactams Polymyxins Aminoglycosides [Penicillin, Cephalosporin] Sulfonamides Tetracyclines Trimethoprim Chloramphenicol Macrolides Oxazolidinone 4  Inhibition of Nucleic Acid Transcription & Replication 5  New class of antibacterials. I. Quinolones -floxacin. Group of synthetic compounds possessing N-1-alkylated 3-carboxy-pyrid-4- one ring fused to another aromatic ring which carries other substituents. Oral & IV. Broad spectrum. Used in ttt of most common UTIs, skin infections, RTIs (sinusitis, pneumonia, bronchitis). 6  Quinolones Mechanism of Action Quinolones inhibit the bacterial DNA gyrase [Topoisomerase II] & Topoisomerase IV enzymes → Inhibit DNA replication & transcription → Cell death Bactericidal N.B. DNA gyrase: Enzyme that relieve the tension [supercoil] produced by unwinding of DNA during replication (inhibit supercoiling) Topoisomerase IV: Enzyme that causes unlinking of interlinked daughter DNA molecules 7 Quinolones Selectivity Quinolones have Selective Toxicity ✓ Human topoisomerase II does not bind quinolones at normal therapeutic doses. Metabolism Glucuronic acid 7-CH2OH metabolite (CH3) conjugation (ACTIVE > parent drug) 7-carboxylic metabolite INACTIVE 7-glucuronide metabolite INACTIVE 8  Quinolones Chemical Incompatibilities Site for chelation (Ca 2+, Mg2+, Al3+, Fe2+) (with divalent & trivalent metals) Less H2O sol complex - not absorbed Less potent ⸫ It is contraindicated to: ✓ Co-administer antacids, hematinic, and tonics. ✓ Consume dairy products soon after quinolone administration. 9 Quinolones Classification 1st 2nd Generation 3rd Generation 4th Generation Generation Nalidixic acid Ciprofloxacin Gatifloxacin Trovafloxacin Norfloxacin Moxifloxacin Ofloxacin Sparfloxacin Lomefloxacin Levofloxacin 10 Quinolones 1st Generation I. Nalidixic Acid Prototype Narrow spectrum √ G –ve bacteria X G +ve, Pseudomonas, anaerobes. Therapeutic use limited to: uncomplicated UTI Unfavorable pharmacokinetics (rapid excretion). Rapid development of resistance - Altered porin proteins due to mutations - Gyrase gene mutations 11  Quinolones 2nd Generation Used mainly for UTIs & infections II. Fluoroquinolones resistant to other antibacterials Better PK properties. 6-Fluoro Lower ability to induce ✓ Increases activity (≠ G-ve) bacterial resistance. ✓ Better PK properties Broad antibacterial activity. Fewer side effects. 7-Piperazine Increases activity & broadens N1-substitution: essential for spectrum (G +ve) activity ↑ CNS side effects (binding to CNS GABA receptors) 12  Quinolones 2nd Generation II. Fluoroquinolones 1. Ciprofloxacin 2. Ofloxacin Oxoquinolone MONOfluorinated Methyl gp → ↑ half life ↓ CNS SE Oxazine * ↓ metabolic rate ≠ Pseudomonas (S)-enantiomer: potent aeruginosa [RTI/UTI] 8-125 times > (R) Racemic mixture 3rd Gen: Levofloxacin (S) Tavanic® Improved metabolic rate 13  Quinolones 2nd Generation II. Fluoroquinolones Ciprofloxacin Used for post-exposure treatment of inhalational Anthrax MONOfluorinated [Anthrax Letters] 2001: Letters containing anthrax spores were mailed to several news media offices and two Democratic U.S. Senators, killing five people and infecting 17 others 14  Quinolones 2nd Generation II. Fluoroquinolones Lomefloxacin Used for chronic DIfluorinated bronchitis & chronic UTI 8-fluoro Piperazine CH3 substitution ↑ activity [↑ absorption & ↑ half-life] ↓ rate of metabolism but causes ↓ CNS SE phototoxicity!! 15  Quinolones 3rd Generation III. Fluoroquinolones ≠ Streptococcus pneumonia ✓ Longer duration [once daily] - HCl salts (oral & parenteral) Reduced phototoxicity. Improved activity ✓ ttt of respiratory infections [longer duration]. [bacterial sinusitis, chronic bronchitis, community-acquired pneumonia (CAP)] 8-methoxy fluoroquinolone azabicylic system Sparfloxacin Moxifloxacin 16  Quinolones 3rd Generation III. Fluoroquinolones 5-Amino Sparfloxacin ✓ Higher potency ≠ G+ve bacteria Good activity ≠ G-ve bacteria [ttt of bronchitis & bacterial gastroenteritis] 8-Fluoro ✓ Incidence of phototoxicity is low Why? Due to presence of amino gp that counteracts the effect of 8-F 17  Quinolones 4th Generation IV. Fluoroquinolones Trifluoronaphthyridine Trovafloxacin azabicyclo gp Broad spectrum ≠ G +ve & G -ve & anaerobes Liver toxicity & pancreatitis! ⸫ Use is limited to life-threatening infections [e.g. life-threatening pneumonia & intra-abdominal infections] ↓ CNS side effects N1-bulky gp decrease GABA binding N.B. Max. therapeutic period should not be > 14 days 18  Quinolones Structure-Activity Relationship C5-amino: ↓ phototoxicity &↑ Activity 6-F: ↑ activity & improve PK EFA Must be aromatic with or without N Double bond is EFA → Reduction: loss of activity ✓ Substit. (C5,6,7*,8): ↑ activity ✓ C7-piperazine: ✓ Alkyl substit. (CH3 < C2H5 < cyclopropyl): EFA ↑ activity & broaden spectrum ✓ Aryl substit: active compounds ↑ GABA affinity - ↑ CNS SE ( which is decreased [2,4-difluorophenyl which is optimum for activity, ↓ CNS SE] by addition of methyl gp on piperazine ring) ✓ Ring condensation (e.g.,: 1,8): ↑ activity & duration. ✓ Methyl/ethyl addition to piperazine or N1-bulky gp: ↓ GABA binding 19 & increase half life  II. Aminoacridines Topical antibacterial for ttt of superficial wounds N.B. Not used systemic bacterial infections … Why? Toxic to host cells Mechanism of Action Direct interaction with bacterial DNA Bacteriostatic (intercalation)→ Disrupt DNA synthesis 20  III. Rifamycins Rifamycin B isolated from streptomyces mediterranei ≠ G+ve Mechanism of Action Non-covalent binding to DNA-dependent RNA polymerase (DDRP)→ inhibit the start of RNA synthesis Rifampicin Bacteriostatic Selective ? Drug binds to a peptide chain not present in the mammalian RNA polymerase 21  Rifamycins Semisynthetic Derivatives Rifampin= Rifampicin Rifapentine Used Once Daily Orange body fluids Used Twice Weekly Orally active, ≠ G +ve & G –ve organisms & T.B. 22 IV. Nitroimidazoles/nitrofurans A. NITROIMIDAZOLE ≠ amebiasis & anaerobic infections Metronidazole Mechanism of Action Drug enters the cell → Reduction of nitro gp to nitroso gp by nitro reductase enzyme: ✓ Formation of free radicals which act on DNA (toxic)→ DNA fragmentation. Bactericidal 23 IV. Nitroimidazoles/nitrofurans A. NITROIMIDAZOLE ≠ amebiasis & anaerobic infections Metronidazole Mechanism of Action Triple therapy of H. Pylori Common side effects include metallic taste. 24 Nitroimidazoles/nitrofurans B. NITROFURANS Mechanism of Action Drug enters the cell → Reduction of nitro gp to nitroso gp by nitro reductase enzyme: ✓ Formation of free radicals which act on DNA (toxic) → DNA fragmentation. Bactericidal 25 Nitroimidazoles/nitrofurans B. NITROFURANS Low incidence of resistance Nitrofurantoin Nifuroxazide Prototype. Broad spectrum ≠ G +ve & G –ve Used in UTIs. bacteria. Used in colitis & diarrhea. 26 Agents Acting on Cell Membrane Structure 27  Polymyxin B Polypeptide derived from Bacillus polymyxa Binds selectively to plasma membranes → Causes leakage of small molecules (e.g. nucleosides) from the cell (Disrupt cell membrane→ Cell death). Dab: α,γ-diaminobutyric acid linked (peptide link) through α-NH2 gp Bactericidal 28 Break 29 Antimetabolites 30  Sulfonamides (Sulpha Drugs) 1932: Red azo dye (Prontosil®) Cure of streptococcal infections in mice ttt of UTI & GIT infections Prototype Prontosil Sulfanilamide Inactive in vitro active in vivo 31 Sulfonamides Mechanism of Action Dihydropteroate synthetase inhibitor Structurally similar to PABA: compete as a substrate in the synthesis of DHFA Only in bacterial cells In both bacteria & mammalian Bacteriostatic Folic Acid Synthesis Inhibitors 32 Sulfonamides Mechanism of Action Dihydropteroate synthetase inhibitor Structurally similar to PABA: Compete as a substrate in the synthesis of DHFA Selectivity Humans do not synthesize folic acid - obtain it from diet Block 1st step of folic acid synthesis Synthesis of thymidine, purine & some aa DNA & RNA synthesis → growth arrest 33 Sulfonamides Synergism ++ Folate Reductase Inhibitor [Trimethoprim] Blocking biosynthesis at more than one step ✓ Synergistic effect [broad spectrum-bactericidal] ✓ Will not develop resistance quickly 34  Sulfonamides Structure-Activity Relationship Aromatic ring & sulfonamide p-amino gp → EFA. Required for activity m- or o- are → inactive ✓ N should be 1ry or 2ry (3ry: inactive) ✓ Ring p-substitution [extra substit. eliminate activity – steric effect] ✓ Replacement with heterocyclic ring: inactive ✓ R2: the only site that can be varied. R1: H→ Active R1: alkyl or alkoxy→ inactive Amino gp & Sulfonamide NO2,NO, NHOH, N=N, NHCOR → converted Directly attached to the aromatic ring in vivo to free NH2→ active 35 Sulfonamides Structure-Activity Relationship Amide Sulfonamide Inactive Active Amides can be used as sulphonamide prodrugs 36  Sulfonamides Side effects 1. Sulpha allergy “fever with urticaria”. 2. Stevens-Johnson Syndrome [severe skin eruption]. 3. Hemolytic anemia. 4. Gastrointestinal distress. 5.Crystalluria. 37 Sulfonamides Side effects Severe Kidney Damage!! Formation of sulfanilamide crystals in the kidney [crystalluria] --- Why? Water soluble at pH above pKa (10.4) Urine pH = 6 (lower during infections): insoluble sulfonamides 38 Sulfonamides Crystalluria 1. Drinking large amounts of water → ↑ urine flow by ↑ rate of glomerular filtration. 2. ↑ pH of urine by alkalinization [using NaHCO3]. 3.↓ pka of the drug by N1-substitution with electron-withdrawing groups (as heterocycles). 4. Sulfa triple therapy (mixing 3 sulfa drugs in low doses (Sulfadiazine + Sulfamerazine + Sulfamethazine ). 39 Sulfonamides Synthesis 40 Sulfonamides Classification Sulfonamides Systemic Intestinal Topical 41 Sulfonamides I. SYSTEMIC Short-acting Sulfisoxazole Sulfathiazole Pyrimidine Sulfapyridine Sulfamethazine 42 Sulfonamides I. SYSTEMIC Intermediate-acting Sulfadiazine Sulfamethoxazole DoC in UTIs + trimethoprim ttt of Toxoplasmosis Cotrimoxazole® ttt of Meningitis Burns (topical) NaHCO3 is co-given 43 Sulfonamides I. SYSTEMIC Long-acting Methoxy groups→ ↑ plasma proteins binding. Sulfadoxine + Pyrimethamine Used RTIs & UTIs (antimalarial) ttt of malaria 44 Sulfonamides II. INTESTINAL Phthalyl Sulfathiazole Prodrug Bacterial hydrolysis in the colon lumen Oral but Non-absorbable [high polarity] ⸫ Used for intestinal infections. 45 Sulfonamides II. INTESTINAL Sulfasalazine Used for ttt of ulcerative colitis, Bacterial diarrhea Prodrug in vivo Reduction 5-Amino Salicylic Acid [5-ASA] Sulfapyridine [anti-inflammatory] [anti-bacterial] 46 Sulfonamides III. TOPICAL Silver Sulfadiazine Sulfacetamide Eye drops for eye infections Topical cream for burns & wounds (conjunctivitis) ≠Pseudomonas Lotion for acne & Seborrheic dermatitis. 47 Sulfonamides Same Pharmacokinetic Properties Trimethoprim ↑↑ selective DHFR inhibitor [100,000 times] ✓ Inhibit DNA synthesis & cell growth. ✓ To avoid the development of resistant strains & broaden the spectrum. Trimethoxy phenyl Diamino pyrimidine 48  Sulfones The most important drugs used in the ttt of leprosy Sulfones Dapsone: Prototype Bacteriostatic M.O.A.: Dihydropteroate Synthetase Inhibitor 49 THANK YOU You can find me at: ⦿ [email protected] 50 Sample Questions Structure A You are provided with structure A one of the β- lactams antibiotics, Choose the correct answer: 1) Structure A belongs to……………. A. Penicillins B. Cephalosporins C. Β-lactamase inhibitors D. Monobactams. 2) M.O.A. of structure A is ……………. A. Protein synthesis inhibitor. B. Cell wall inhibitor. C. Nucleic acid synthesis inhibitor. D. Cell membrane disruption. Sample Questions Structure A 3) Structure A inhibits……………………. Enzyme. A. DHP Synthase B. DHF reductase C. Transpeptidase D. Penicillinase 4) Structure A is ……………. A. Acid stable. B. Broad spectrum. C. Β-lactamase resistant. D. Both A & B. Sample Questions Structure A 5) The double ester prodrug of structure A has the advantage of………………. A. Higher oral BA B. β- lactamase resistance C. Higher water solubility D. None of the above 6) To make structure A an acid & β-lactamase resistant drug you can replaced the encircled group with ……………. A. Phenoxy group. B. Isoxazole ring. C. 2- Methoxy groups. D. Thiophene ring. Sample Questions Structure A 7) …………..is responsible for the broad spectrum of activity of structure A A. COOH group. B. Phenyl ring. C. NH2 group. D. Thiazolidine ring. 8) Sultamcillin is a prodrug of sulbactam with Structure A in order to…………………. A. Enhance water solubility. B. Enhance oral BA. C. Enhance Β-lactamase resistance. D. Both B & C. Sample Questions Structure A 9) Which part of structure A is Not EFA……….. A. Acyl side chain. B. COOH group. C. S atom. D. β- lactam ring. 10) Structure A is…………………. A. Bactericidal. B. Bacteriostatic. C. All of the above. D. None of the above.